One type of transmembrane agent delivery is electrotransport, ie, electrically assisted transmembrane delivery. "Electrotransport" refers generally to the passage of a substance through a body surface or membrane, such as skin, mucous membranes, or nails, at least partially induced by the passage of an electrical current. For example, a therapeutic agent may be introduced into the human body by electrotransport. One widely used electrotransport process, iontophoresis, involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport, involves the movement of a liquid through a biological membrane (eg, skin) under the influence of an electric field. Another type of electrotransport, electroporation, involves the transport of an agent through transiently-existing pores formed in a biological membrane under the influence of an electric field. In any given electrotransport process, however, more than one of these processes may be occurring simultaneously to a certain extent. Accordingly, the term "electrotransport", is used herein in its broadest possible interpretation so that it includes the electrically induced or enhanced transport of an agent, which may be charged or uncharged, or a mixture thereof, regardless of the specific mechanism(s) of transport.
More recently, a number of United States patents have issued in the electrotransport field, indicating a renewed interest in this mode of drug delivery. For example, U.S. Pat. No. 3,991,755 issued to Vernon et al; U.S. Pat. No. 4,141,359 issued to Jacobsen et al; U.S. Pat. No. 4,398,545 issued to Wilson; and U.S. Pat. No. 4,250,878 issued to Jacobsen disclose examples of electrotransport devices and some applications thereof. The electrotransport process has been found to be useful in the transdermal administration of medicaments or drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, insulin and many other drugs. Perhaps the most common use of electrotransport is in diagnosing cystic fibrosis by delivering pilocarpine salts by electrotransport. The pilocarpine stimulates sweat production; the sweat is collected and analyzed for its chloride content to detect the presence of the disease.
In presently known electrotransport devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by electrotransport. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, eg, a battery. For example, if the ionic substance to be delivered into the body is positively charged (ie, a cation), then the anode will be the active electrode and the cathode will serve to complete the circuit. If the ionic substance to be delivered is negatively charged (ie, an anion), then the cathode will be the active electrode and the anode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver drugs of opposite charge into the body. In such a case, both electrodes are considered to be active or donor electrodes. For example, the anode can deliver a positively charged ionic substance into the body while the cathode can deliver a negatively charged ionic substance into the body.
It is also known that electrotransport delivery devices can be used to deliver an uncharged drug or agent into the body. This is accomplished by a process called electroosmosis. Electroosmosis is transdermal flux of a liquid solvent (eg, the liquid solvent containing the uncharged drug or agent) which is induced by the presence of an electric field imposed across the skin by the donor electrode. As used herein, the term "electrotransport" applies equally to electrically powered devices which deliver charged/ionic agents by electromigration as well as to electrically powered devices which deliver uncharged/nonionic agents by electroosmosis.
Furthermore, existing electrotransport devices generally require a reservoir or source of the beneficial agent (which is preferably an ionized or ionizable agent or a precursor of such agent) to be delivered by electrotransport into the body. Examples of such reservoirs or sources of ionized or ionizable agents include a pouch as described in the previously mentioned Jacobsen U.S. Pat. No. 4,250,878, or a pre-formed gel body as described in Webster U.S. Pat. No. 4,382,529 and Ariura et al U.S. Pat. No. 4,474,570. Such drug reservoirs are electrically connected to the anode or the cathode of an electrotransport device to provide a fixed or renewable source of one or more desired agents.
More recently, electrotransport delivery devices have been developed which utilize complex electrical circuits in order to perform a number of functions. These complex circuits include pulsing circuits for delivering a pulsed current, timing circuits for delivering drugs over predetermined timing and dosing regimens, feedback regulating circuits for delivering drugs in response to a sensed physical parameter, and polarity controlling circuits for periodically reversing the polarity of the electrodes. See for example, Tapper et al U.S. Pat. No. 4,340,047; Lattin U.S. Pat. No. 4,456,012; Jacobsen U.S. Pat. No. 4,141,359; and Lattin et al U.S. Pat. No. 4,406,658.
Some electrotransport devices have used a simple DC power source, typically a battery, electrically connected in series with the two electrodes. See for example, Ariura et al, U.S. Pat. No. 4,474,570. Other devices have used more complex circuits to provide a current source for connection to the electrodes, and at least one of them (Jacobson et al, U.S. Pat. No. 4,141,359) proposes monitoring the electrical impedance of the skin contacted by the electrodes. A circuit monitors current flow and voltage across the electrodes and automatically triggers a shutdown circuit when impedance readings are outside predetermined limits, to thereby prevent excessive voltage build-up and the accompanying dangers of shock and burns. While the Jacobsen circuit is suitable for electrotransport devices which apply electric current continuously once activated, it is not well suited for electrotransport devices which apply electric current discontinuously once placed on the body and activated. Examples of electrotransport devices which discontinuously apply electric current to the patient include the device disclosed in Sibalis U.S. Pat. No. 5,013,293 (eg, electrotransport delivery of LHRH for 6 minutes out of every hour to mimic a normal healthy body's natural release of LHRH); electrotransport delivery of insulin before mealtimes; and patient-activated electrotransport delivery of pain killing agents (eg, narcotic analgesics) to control pain (eg, post-operative pain, chronic cancer pain, etc).